Methods of preventing progression to type 2 diabetes melitus

ABSTRACT

The present invention provides compositions and methods for delaying or preventing progression to type 2 diabetes mellitus in individuals with prediabetes and metabolic syndrome.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/049,989, filed Jul. 31, 2018, which is a continuation of U.S.application Ser. No. 15/639,972, filed Jun. 30, 2017, now U.S. Pat. No.10,058,532, which is a continuation of U.S. application Ser. No.14/509,297, which was filed on Oct. 8, 2014, now U.S. Pat. No.9,724,327, which claims priority to, and the benefit of, U.S.Provisional Patent Application Ser. No. 61/888,490, filed Oct. 8, 2013,the contents of each of these applications are herein incorporated byreference in their entireties.

FIELD OF THE INVENTION

The disclosure relates to, among other things, methods for preventingprogression to type 2 diabetes mellitus in individuals with prediabetesand metabolic syndrome. Individuals are treated with a combination ofphentermine and topiramate extended release (PHEN/TPM ER), which hasbeen shown to induce weight loss and improve glycemia in overweightsubjects and obese subjects with one or more weight relatedcomorbidities. Treatment with PHEN/TPM ER results in markedly reducedprogression to type 2 diabetes in overweight or obese patients withprediabetes and/or metabolic syndrome and results in improvements inmultiple cardiometabolic disease risk factors.

BACKGROUND OF THE INVENTION

The increased prevalence of type 2 diabetes mellitus (also referred toherein as T2DM or type 2 diabetes), together with its burden of patientsuffering and societal costs, underscores the importance of findingeffective strategies for both treatment and prevention. T2DM ischaracterized by high blood glucose levels caused by a lack of insulinor the body's inability to efficiently use insulin. Two clinicalconstructs for identifying individuals at high risk of future T2DM areprediabetes and metabolic syndrome (MetS). Prediabetes is a state ofdysglycemia characterized by impaired fasting glucose (IFG) and/orimpaired glucose tolerance (IGT). A diagnosis of prediabetes may be madeif an individual's glucose is higher than normal but not high enough tobe diagnosed as diabetes. It is estimated that 79 million Americans aged20 years or older have prediabetes, with 25% progressing to T2DM within3-5 years (Nathan, et al. Diabetes Care. 2007; 30(3):753-759). ENREF4T2DM is associated with abdominal obesity and insulin resistance(diagnostic criteria were established by the Advanced Treatment PanelIII of the National Cholesterol Education Program). There are a numberof risk factors that increase an individual's risk for T2DM including,for example, being over age 45, being overweight or obese, having aparent, brother or sister with diabetes, a family background that isAfrican American, Alaska Native, American Indian, Asian American,Hispanic/Latino, or Pacific Islander, having a history of gestationaldiabetes, giving birth to a baby weighing more than 9 pounds, bloodpressure of 130/85 or 140/90 or higher, HDL lower than 35 or lower than40 (for males) or lower than 50 for females or triglyceride level above150 or above 250, inactive lifestyle, polycystic ovary syndrome, aprevious diagnosis of prediabetes, for example HbA1c level of 5.7 to6.4%, impaired fasting glucose (IFG) or impaired glucose tolerance(IGT), another clinical conditions associated with insulin resistance,such as a condition called acanthosis nigricans, characterized by adark, velvety rash around my neck or armpits, or a history ofcardiovascular disease. The more of these risk factors present in apatient the higher the patient's risk of developing T2DM. HbA1c refersto glycated haemoglobin (A1c), which identifies average plasma glucoseconcentration and can be used to get an overall picture of what anindividual's average blood sugar levels have been over a period of time.

MetS is a cluster of risk factors for cardiovascular disease includingthe following risk factors (1) a large waistline (at least 102 cm or 40inches for males and at least 88 cm or 35 inches for females), alsoreferred to as abdominal obesity, (2) high triglyceride levels (greaterthan 150 or 250) or using medicine to treat high triglycerides, (3) lowHDL cholesterol levels (lower than 35 or lower than 40 (for males) orlower than 50 for females) or using medicine to treat low HDLcholesterol, (4) high blood pressure (above 130/85 or above 140/90) orusing medicine to treat high blood pressure, and (5) high fasting bloodsugar (also referred to as impaired fasting glucose (IFG)) or usingmedicine to treat high blood sugar ((See Alberti K G, et al.,Circulation 2009; 120(16):1640-1645; Bakris G, et al., Diabetes ObesMetab. 2009; 11(3):177-187; Expert Panel on Detection, Evaluation, andTreatment of High Blood Cholesterol in Adults, JAMA 2001;285(19):2486-2497; and Grundy S M, et al. Circulation 2005;112(17):2735-2752). A diagnosis of MetS generally required a diagnosisof at least three of the five metabolic risk factors listed above.Individuals with MetS are at a 5-fold increased risk of developing T2DM(Alberti K G, et al. 2009). Because IFG is one of the traits used toidentify MetS, overlap with criteria for prediabetes exists, and therisk of progression to T2DM is further increased in individuals whosatisfy the criteria for both MetS and prediabetes. Lorenzo C, et al.,Diabetes Care. 2003; 26(11):3153-3159. Thus, effective treatment ofthese at-risk individuals is important for the prevention of T2DM.

Sustained loss of 5% to 10% of body weight in obese and overweightpatients has proven to be effective in preventing progression fromprediabetes and MetS to T2DM and also ameliorates the cardiometabolicdisease process, as shown by an increase in insulin sensitivity and areduction in cardiovascular disease risk factors. However, achievingsustained weight loss at a clinically meaningful level sufficient toreduce risk remains a challenge for many patients. The primary approachto treating obesity and its related complications involves lifestylemodifications, including reductions in caloric intake (by 500-1000calories/day) combined with increases in physical activity. Bariatricsurgery can also be an effective weight-loss option for patients meetingspecific criteria and may reduce the incidence of T2DM, Colquitt J L, etal., Cochrane Database Syst Rev. 2009; 15(2):CD003641, Hussain S S,Bloom S R, Postgrad Med. 2011; 123(1):34-44 and Carlsson L M, et al., NEngl J Med. 2012; 367(8):695-704 but the approach entails risksassociated with surgery, nutritional deficiencies, and weight regain insome patients. Kofman M D, et al., Obesity (Silver Spring). 2010;18(10):1938-1943.

In patients for whom lifestyle changes alone are insufficient andbariatric surgery is not an option, pharmacotherapies may be considered.Phentermine and topiramate extended-release (PHEN/TPM ER; QSYMIA®;VIVUS, Inc., Mountain View, Calif.) has been shown to induce significantweight loss when combined with lifestyle modification inoverweight/obese adults. See, for example, Allison D B, et al., Obesity(Silver Spring), 2012; 20(2):330-342. The CONQUER study assessedeffectiveness of PHEN/TPM ER for weight loss in overweight/obese adultswith two or more weight-related comorbidities over 56 weeks(ClinicalTrials.gov, NCT00553787)(Gadde K M, et al., Lancet. 2011;377(9774):1341-1352) and was followed by SEQUEL, a 52-week blindedextension study (ClinicalTrials.gov, NCT00796367)(Garvey W T, et al., AmJ Clin Nutr. 2012; 95(2):297-308). In order to assess the ability ofPHEN/TPM ER to reduce progression to T2DM and improve manifestations ofcardiometabolic disease in patients at high risk of developing T2DM, asubpopulation of patients meeting the criteria at baseline forprediabetes and/or MetS who elected to enroll in SEQUEL was analyzed.

In addition to being related to incidence of various diseases, obesitycan increase the risk of death from hypertension, dyslipidemia,diabetes, such as type II diabetes mellitus, coronary artery disease,heart disease, stroke, gallbladder disease, osteoarthritis, liverdisease, and cancers, such as endometrial, breast, prostate, and coloncancers (see, for example, Pi-Sunyer et al. Postgrad Med2009:121:21-33).

Topiramate, a sulfamate-substituted monosaccharide with the chemicalname 2,3,4,5-bis-O-(1methyletylidene)-β-D-fructopyranose sulfamate, hasbeen reported for use in treating obesity and promoting weight loss, forexample, in U.S. Pat. Pub. 2009/0304785, and is also marketed fortreating migraine headaches and seizure related disorders. A variety ofdosages of topiramate can be used for these purposes, depending on theweight, age, gender, and other characteristics of the subject. Althoughefficacious for these purposes, topiramate is known to have harmful sideeffects in some subjects. Furthermore, some subjects do not respond totopiramate treatment for obesity. Thus, there is a need for a dosingregimen for topiramate that minimizes subjects' exposure to topiramatewhile providing one or more indications of whether a particular subjectis likely to experience harmful side effects and/or respond totopiramate treatment. The embodiments described herein can meet theseand other needs.

SUMMARY OF THE INVENTION

Methods for delaying the progression of patients at risk for developingtype 2 diabetes mellitus are disclosed. The methods compriseadministering to a patient that has been diagnosed with prediabetes orMetS, or are otherwise identified as being at high risk to develop T2DM,an oral dosage form of immediate release phentermine and controlledrelease topiramate.

Preferred daily doses include 3.75 mg immediate release phentermine incombination with 23 mg controlled release topiramate (3.75/23), 7.5 mgimmediate release phentermine in combination with 46 mg controlledrelease topiramate (7.5/46), 11.25 mg immediate release phentermine incombination with 69 mg controlled release topiramate (11.25/69), and 15mg immediate release phentermine in combination with 92 mg controlledrelease topiramate (15/92).

The combination of phentermine and topiramate may be administered to thepatient for a period of weeks, months or years and patients may increasedoses over time. In one aspect the patient starts with a daily dose of3.75/23 for 1 to 2 weeks then increases the dose to 7.5/46. The patientmay maintain that dose for 1 to 3 months and then either stay on the7.5/46 dose for up to 2 years or longer or increase to the 15/92 dose.Some patients, rather than increasing directly to the 15/92 dose fromthe 7.5/46 dose will take the 11.25/69 dose for a period of 1 to 2 weeksbefore moving to the 15/92 dose.

In a preferred aspect the patient has been identified as being at highrisk of developing type 2 diabetes and the treatment prevents or delaysthe onset of type 2 diabetes. For those patients that then experience anonset of type 2 diabetes, the method of treatment prior to the onsetreduces the severity of the symptoms experienced by the patientfollowing the onset of type 2 diabetes. Although in many cases the atrisk patient will be overweight (BMI greater than 25) or obese (BMI of30 or higher), patients having normal weight (BMI 25 or less) that areat risk for diabetes may also benefit from the disclosed method oftreatment.

Individuals may be diagnosed with prediabetes if they have one of thefollowing: (i) HbA1c levels that are at least 5.7% but not greater than6.4%; (ii) plasma glucose levels of not more than 11 mmol/L (200 mg/dl)but at least 7.8 mmol/L (140 mg/dl) as measured in an OGTT screeningtest (impaired glucose tolerance); or (iii) blood glucose levels lessthan or equal to 7.0 mmol/L (126 mg/dl) but higher than 6.1 mmol/L (110mg/dl) (impaired fasting glucose).

Individual may be diagnosed with MetS if they have at least 3 of thefollowing: (i) waist circumference of at least 102 cm if the patient ismale or at least 88 cm if the patient is female; (ii) triglyceride levelof 150 mg/dL or higher; (iii) HDL cholesterol levels below 40 mg/dL ifthe patient is a male or below 50 mg/dL if the patient is a female ortaking lipid lowering medication; (iv) systolic blood pressure of 130 mmHg or greater, or diastolic blood pressure of 85 mm Hg or greater ortaking antihypertensive medication; and (v) fasting blood glucose levelsof 100 mg/dL or greater or taking medication for elevated glucose.Patients that have been diagnosed with MetS may achieve remission ofMetS if they no longer meet at least 3 of the identified criteria.

In some aspects the method may be used to lower hs-CRP values(high-sensitivity C-Reactive Protein) to 3.0 mg/L or less (higher levelsare indicative of high risk for cardiovascular disease), lowerfibrinogen levels to 400 mg/dL or less, and increase adiponectinconcentrations from the starting levels for the patient prior totreatment, for example to greater than 20 mcg/mL for males and greaterthan 22 mcg/mL for females, in patients at risk for developing T2DM. Themethod of treatment may further achieve in patients diagnosed withprediabetes or MetS an improvement in at least one of the following:fasting glucose levels, fasting insulin levels, 2-hour post-oral glucosetolerance test (OGTT) glucose levels, fasting triglycerides levels andHDL-C levels.

Although methods and materials similar or equivalent to those describedherein can be used in the practice or testing of the present invention,suitable methods and materials are described below. All publications,patent applications, patents, and other references mentioned herein areincorporated by reference in their entirety. The references cited hereinare not admitted to be prior art to the claimed invention. In the caseof conflict, the present specification, including definitions, willcontrol. In addition, the materials, methods, and examples areillustrative only and are not intended to be limiting. Other featuresand advantages of the invention will be apparent from the followingdetailed description and claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows percent weight loss from baseline to week 108 in the cohortwith prediabetes and/or metabolic syndrome at baseline assessed usingleast-squares mean percent weight loss in the intent-to-treat (ITT)population of subjects with prediabetes and/or metabolic syndrome.

FIG. 2A shows cumulative incidence rates of type 2 diabetes at study end(Kaplan-Meier) in the prediabetes and/or Metabolic Syndrome cohort ofthe SEQUEL study from baseline to week 108 (ITT).

FIG. 2B shows annualized incidence rates of type 2 diabetes at study endin the prediabetes cohort and the Metabolic Syndrome cohort for theSEQUEL study (ITT).

FIG. 2C shows the relationship between weight loss and type 2 diabetesincidence at study end in the prediabetes and/or Metabolic Syndromecohort of the SEQUEL study (ITT-MI).

FIG. 3A shows least-squares mean percent change from baseline in glucosein subjects in the prediabetes and/or Metabolic Syndrome cohort.

FIG. 3B shows least-squares mean percent change from baseline in insulinin the prediabetes and/or Metabolic Syndrome cohort.

FIG. 3C shows least-squares mean percent change from baseline in lipidparameters in the prediabetes and/or Metabolic Syndrome cohort.

FIG. 4 shows a diagram of the trial profile.

DETAILED DESCRIPTION

In this application, including the appended claims, the singular forms“a,” “an,” and “the” are often used for convenience. However, it shouldbe understood that these singular forms include the plural unlessotherwise specified. It should also be understood that all patents,publications, journal articles, technical documents, and the like,referred to in this application, are hereby incorporated by reference intheir entirety and for all purposes.

Unless otherwise defined, all terms used in this application should begiven their standard and typical meanings in the art, and are used asthose terms would be used by a person of ordinary skill in the art atthe time of the invention.

“Active agent” as used herein encompass not only the specified molecularentity but also its pharmaceutically acceptable, pharmacologicallyactive analogs, including, but not limited to, salts, esters, amides,prodrugs, conjugates, active metabolites, and other such derivatives,analogs, and related compounds as will be discussed infra. Therefore,reference to “phentermine,” for example, encompasses not onlyphentermine per se but also salts and other derivatives of phentermine,e.g., phentermine hydrochloride. It is to be understood that whenamounts or doses are specified, that those amounts or doses refer to theamount or dose of active agent per se and not to a salt or the like. Forexample, when it is indicated that a dose or amount of phentermine is7.5 mg, that would correspond to 9.84 phentermine hydrochloride and not7.5 phentermine hydrochloride.

“Administering” as used herein includes to any route of administration,for example, oral, parenteral, intramuscular, transdermal, intravenous,inter-arterial, nasal, vaginal, sublingual, subungal, etc. Administeringcan also include prescribing a drug to be delivered to a subject, forexample, according to a particular dosing regimen, or filling aprescription for a drug that was prescribed to be delivered to asubject, for example, according to a particular dosing regimen.

“Body Mass Index” or “BMI” as used herein is an index ofweight-for-height that is commonly used to classify overweight andobesity in adults. BMI may be calculated by multiplying an individual'sweight, in kilograms, by height, in meters. Currently the CDC and WHOdefine obesity as having a BMI of 30 or higher. A BMI between 25 and29.9 is considered overweight. A BMI over 40 is sometimes characterizedas morbidly obese. Individuals having a BMI between 30 and 35 may alsobe referred to as moderately obese, from 35 to 40 severely obese andover 40 very severely obese.

A “daily dose” of a particular material refers the amount of thematerial administered in a day. A daily dose can be administered as asingle dose or as multiple doses. When a daily dose is administered asmultiple doses, the daily dose is the sum of the amount of materialadministered in all of the multiple doses that are administered over thecourse of one day. For example, a daily dose of 12 mg can beadministered in a single 12 mg dose once per day, in 6 mg dosesadministered twice per day, in 4 mg doses administered three times perday, in 2 mg doses administered six times per day, etc. The multipledoses can be the same or different doses of the material, unlessotherwise specified. When a daily dose is administered as multipledoses, the multiple doses can be administered by the same or differentroute of administration, unless otherwise specified. Thus, a daily doseof 12 mg can include, for example, a 10 mg intramuscular dose and a 2 mgoral dose administered over the course of one day.

The term “dosage form” denotes any form of a pharmaceutical compositionthat contains an amount of active agent sufficient to achieve atherapeutic effect with a single administration. When the formulation isa tablet or capsule, the dosage form is usually one such tablet orcapsule, although this is not required unless otherwise specified. Thefrequency of administration that will provide the most effective resultsin an efficient manner without overdosing will vary with thecharacteristics of the particular active agent, including both itspharmacological characteristics and its physical characteristics, suchas hydrophilicity.

The term “controlled release” refers to a drug-containing formulation orfraction thereof in which release of the drug is not immediate, i.e.,with a “controlled release” formulation, administration does not resultin immediate release of the drug into an absorption pool. The term isused interchangeably with “nonimmediate release” as defined inRemington: The Science and Practice of Pharmacy, Nineteenth Ed. (Easton,Pa.: Mack Publishing Company, 1995). In general, the term “controlledrelease” as used herein includes sustained release, modified release anddelayed release formulations.

The term “sustained release” (synonymous with “extended release”) isused in its conventional sense to refer to a drug formulation thatprovides for gradual release of a drug over an extended period of time,and that preferably, although not necessarily, results in substantiallyconstant blood levels of a drug over an extended time period. The term“delayed release” is also used in its conventional sense, to refer to adrug formulation which, following administration to a patient provides ameasurable time delay before drug is released from the formulation intothe patient's body.

Administration of one compound “with” a second compound, as used herein,includes but is not limited to cases where the two compounds areadministered simultaneously or substantially simultaneously. Forexample, administration of a first compound with a second compound caninclude administering the first compound in the morning andadministering the second compound in the evening, as well asadministering the first and second compounds in the same dosage form orin two different dosage forms that at the same or nearly the same time.

“Topiramate” as used herein includes not only the chemical compound2,3:4,5-di-O-isopropylidene-β-D-fructopyranose sulfamate, but also allstereoisomers, such as enantiomers and diasteriomers, thereof, as wellas salts, mixed salts, polymorphs, solvates, including mixed hydratesand mixed solvates, of one or more stereoisomers or mixtures ofstereoisomers. The molecular formula is C₁₂H₂₁NO₈S and its molecularweight is 339.4. Topiramate is a white to off-white crystalline powderwith a bitter taste. It is freely soluble in methanol and acetone,sparingly soluble in pH 9 to pH 12 aqueous solutions and slightlysoluble in pH 1 to pH 8 aqueous solutions.

“Phentermine” as used herein includes not only the chemical compound2-methyl-1-phenylpropan-2-amine, but also all stereoisomers, such asenantiomers and diasteriomers, thereof, as well as salts, mixed salts,polymorphs, solvates, including mixed hydrates and mixed solvates, ofone or more stereoisomers or mixtures of stereoisomers. The chemicalname of phentermine hydrochloride is α,α-dimethylphenethylaminehydrochloride. The molecular formula is C₁₀H₁₅N.HCl and its molecularweight is 185.7 (hydrochloride salt) or 149.2 (free base). A dosage of3.75 mg phentermine is preferably in the form of 4.92 mg phenterminehydrochloride and similarly a dosage of 7.5 mg phentermine is preferablyin the form of 9.84 mg phentermine hydrochloride, a dosage of 11.25 mgphentermine is preferably in the form of 14.76 mg phenterminehydrochloride and a dosage of 15 mg phentermine is preferably in theform of 19.68 mg phentermine hydrochloride.

A “subject” or multiple “subjects” can be members of any species,typically human. The subjects of all experiments and studies discussedherein were human except when otherwise indicated.

The term “sustained release” (synonymous with “extended release”) isused in its conventional sense to refer to a drug formulation thatprovides for gradual release of a drug over an extended period of time,and that preferably, although not necessarily, results in substantiallyconstant blood levels of a drug over an extended time period. The term“delayed release” is also used in its conventional sense, to refer to adrug formulation which, following administration to a patient provides ameasurable time delay before drug is released from the formulation intothe patient's body.

The term “unit dosage forms” as used herein refers to physicallydiscrete units suited as unitary dosages for the individuals to betreated. That is, the compositions are formulated into discrete dosageunits each containing a predetermined, “unit dosage” quantity of anactive agent calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical carrier. The specificationsof unit dosage forms of the invention are dependent on the uniquecharacteristics of the active agent to be delivered. Dosages can furtherbe determined by reference to the usual dose and manner ofadministration of the ingredients. It should be noted that, in somecases, two or more individual dosage units in combination provide atherapeutically effective amount of the active agent, e.g., two tabletsor capsules taken together may provide a therapeutically effectivedosage of topiramate, such that the unit dosage in each tablet orcapsule is approximately 50% of the therapeutically effective amount.

A suitable daily dose of topiramate extended-release is in the range of10 mg to 150 mg. For example, 10 mg, 20 mg, 30 mg, 60 mg, 90 mg, 120 mg,150 mg, or the like is administered to a patient as a daily dosage. Inanother example, 23 mg, 46 mg, 69 mg and 92 mg or the like isadministered to a patient as a daily dosage. In certain embodiments, thedaily dosage of topiramate extended release is in the range of 10 mg to100 mg. Each of the aforementioned “daily dosages” is generally althoughnot necessarily administered as a single daily dose.

A suitable daily dose of phentermine is in the range of 3 mg to 30 mg.For example, 3 mg, 5 mg, 8 mg, 10 mg, 12 mg, 15 mg, 20 mg, 25 mg, 30 mg,or the like is administered to a patient as a daily dosage. In anotherexample, 3.75 mg, 7.5 mg, 11.25 mg and 15 mg or the like is administeredto a patient as a daily dosage. Each of the aforementioned “dailydosages” is generally although not necessarily administered as a singledaily dose.

Daily doses of PHEN/TPM ER that available include 3.75 mg phenterminewith 23 mg topiramate extended-release, 7.5 mg phentermine with 46 mgtopiramate extended-release, 11.25 mg phentermine with 69 mg topiramateextended-release, and 15 mg phentermine with 92 mg topiramateextended-release.

The patient may receive a specific dosage of PHEN/TPM ER over a periodof weeks, months, or years, e.g., 1 week, 2 weeks, 3 weeks, 1 month, 2months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9months, 10 months, 11 months, 1 year, 2 years, 3 years, 4 years, 5 yearsand the like. In some embodiments the patient starts at one dose for aperiod of time and then increases doses after a period.

In one embodiment, a daily dose of phentermine can be administered withone or more of daily dose of about 23 mg topiramate, the daily dose ofabout 46 mg topiramate, the daily dose of about 69 mg topiramate, andthe daily dose of about 92 mg topiramate. In another embodiment, a dailydose of about 3.75 mg of phentermine can be administered with the dailydose of about 23 mg of topiramate. In yet another embodiment, a dailydose of about 7.5 mg of phentermine can be administered with the dailydose of about 46 mg of topiramate. In still another embodiment, a dailydose of about 11.25 mg phentermine can be administered with the dailydose of about 69 mg of topiramate. In a further embodiment, a daily doseof about 15 mg of phentermine can be administered with the daily dose ofabout 92 mg of topiramate.

In a particular embodiment, phentermine can be administered in animmediate release form. In a specific embodiment, the topiramate can beadministered in a controlled release form. In other embodiments, thecontrolled release form is a polymer coated bead. In an additionalembodiment, phentermine can be administered in an immediate release formand the topiramate can be administered in a controlled release form. Insome embodiments, the phentermine and the topiramate are administered ina single unit dosage form having a controlled release topiramate portionand an immediate release phentermine portion.

Treatment with PHEN/TPM ER may be used as a method for slowingprogression, delaying onset of, or treating a metabolic disorder;improving glycemic control and/or for reducing fasting plasma glucose,postprandial plasma glucose, and/or glycosylated hemoglobin HbA1c;preventing, slowing, delaying, or reversing progression from impairedglucose tolerance, insulin resistance, and/or metabolic syndrome to type2 diabetes mellitus; preventing, slowing progression, delaying, ortreating complications of diabetes mellitus; preventing or treating thedegeneration of pancreatic beta cells and/or for improving and/orrestoring the functionality of pancreatic beta cells and/or restoringthe functionality of pancreatic insulin secretion; or for maintainingand/or improving the insulin sensitivity and/or for treating orpreventing hyperinsulinemia and/or insulin resistance, by administeringto a patient a combination of phentermine and topiramate.

High-risk overweight or obese patients with prediabetes and/or metabolicsyndrome who were taking PHEN/TPM ER over a two year period experiencedreductions of up to 78.7% in the annualized incidence rate of type 2diabetes, in addition to losing weight. The American Association ofClinical Endocrinologists recognizes obesity and prediabetes assignificant risk factors for progression to diabetes and associatedcomplications.

These data demonstrate that treatment with PHEN/TPM ER is highlyeffective in preventing progression to diabetes in an at-riskpopulation, and underscores the observation that 10% weight lossachieves beneficial effects on metabolism and risk factors in patientswith prediabetes and metabolic syndrome.

Treatment with PHEN/TPM ER may also reduce the severity of symptoms inpatients that do progress to diabetes despite treatment PHEN/TPM ERprior to onset of diabetes. Symptoms of diabetes that may be reduced byPHEN/TPM ER treatment include, for example, polydipsia, polyphagia,polyuria, blurred vision, dizziness, extreme tiredness, genital itching,nausea and vomiting, frequent yeast infections, psoriasis, and slowhealing of wounds.

Participants in the study included 475 high-risk overweight or obesepatients with prediabetes and/or metabolic syndrome at baseline from thetwo-year SEQUEL study, for their progression to type 2 diabetes andtheir changes in cardiometabolic parameters. After 108 weeks, it wasobserved that patients receiving PHEN/TPM ER, in conjunction withlifestyle modifications, experienced significant weight loss along withmarkedly reduced progression to type 2 diabetes and improvements inmultiple cardiometabolic disease risk factors.

Subjects in the PHEN/TPM ER Recommended dose (7.5 mg/46 mg) and Top dose(15 mg/92 mg) treatment groups experienced reductions of 70.5% and 78.7%in the annualized incidence rate of type 2 diabetes, respectively,versus placebo, which was related to degree of weight lost (10.9% and12.1%, respectively, versus 2.5% with placebo; ITT-MI; P<0.0001).PHEN/TPM ER therapy was well tolerated by this subgroup over two years.

Subgroup analysis of patients participating in the CONQUER and SEQUELstudies was performed as described herein. (See also, Garvey et al.,Diabetes Care 2014; 37(4):912-21). The analysis allowed for assessmentof the ability of PHEN/TPM ER to prevent progression to type 2 diabetesin at-risk patients during a 2-year period. In patients with prediabetesand/or MetS, PHEN/TPM ER was highly effective in inducing and sustainingweight loss and had a profound effect on prevention of type 2 diabetes,as measured by cumulative and annualized incidence rates. There was a71% and 79% reduction in progression to type 2 diabetes among patientstreated with 7.5/46 and 15/92 compared with placebo over 108 weeks.Weight loss associated with PHEN/TPM ER treatment may be maintainedbeyond 2 years and may lead to sustained lower rates of progression totype 2 diabetes as compared with patients treated with placebo. Mostcases of type 2 diabetes in PHEN/TPM ER-treated patients occurred in thefirst year of the study, whereas cases continued to accumulate into thesecond year in the placebo group (FIG. 2A); thus, the difference incumulative incidence between the PHEN/TPM ER and placebo groups, and therelative degree of type 2 diabetes prevention, may continue to increaseover time.

The ability to prevent type 2 diabetes correlated with the magnitude ofweight loss, independent of randomization group. The annualizedincidence rate for type 2 diabetes was progressively reduced as weightloss increased, with the lowest value realized at ≥15% weight loss,suggesting that greater weight loss is associated with greater benefits.Previous studies of lifestyle intervention have also indicated that thedegree of weight loss was an important determinant of type 2 diabetesprevention (Hamman R F, et al., Diabetes Care 2006; 29(9):2102-2107).The results discussed herein are in agreement with demonstrate thatgreater weight loss leads to greater reductions in the rate of type 2diabetes. All categories with ≥5% weight loss experienced greaterreductions in cumulative type 2 diabetes incidence when compared withthe weight loss category of <5%. Thus, while modest weight loss ofapproximately 5%, as recommended by the ADA, is beneficial, greaterdegrees of weight loss appear to lead to greater prevention of type 2diabetes.

Although the present study was limited to 2 years, the DPP, FinnishDiabetes, (Laaksonen D E, et al., Diabetes 2005; 54(1):158-165) and DaQing studies all demonstrated that after changes in or discontinuationof active treatment, the incidence of new type 2 diabetes diagnosesremained reduced compared with placebo or usual care over longer periodsof follow-up (Pan X R, et al., Diabetes Care 1997; 20(4):537-544,Lindstrom J, et al., Lancet 2006; 368(9548): 1673-1679, Christophi C A,et al., Lancet 2009; 374(9702): 1677-1686 and Li G, et al., Lancet 2008;371(9626):1783-1789. Based on these data, reduced rates of type 2diabetes should continue to be observed in the PHEN/TPM ER treatmentarms compared with placebo, even after discontinuation of drugtreatment.

Importantly, weight loss and prevention of type 2 diabetes as aconsequence of PHEN/TPM ER therapy were accompanied by an increase ininsulin sensitivity, as manifested by reduced glucose and insulinvalues, and improvements in cardiometabolic risk factors (bloodpressure, waist circumference, triglycerides, and HDL-C). Furthermore,systemic inflammation, as measured by hs-CRP and fibrinogen at week 56,was reduced, and levels of the insulin-sensitizing adipocytokine,adiponectin, at week 56, were increased. Since insulin resistance,dyslipidemia, inflammation, and dysregulated secretion of adipocytokinesare all hallmarks of cardiometabolic disease, these findings areindicative of the potential reversal of this pathophysiologic process.

It should be noted that in clinical trials assessing PHEN/TPM ER, allpatients received advice on lifestyle modification, and the currentbenefits reflect the combination of PHEN/TPM ER and the lifestyleprogram (Gadde et al., Lancet 2011, Garvey et al., Am J Clin Nutr 2012;95(2):297-308). The LEARN program is similar to the DPP lifestyleintervention in that it strongly emphasizes behavior modification;however, the LEARN program has a less stringent calorie-reductionrequirement (decrease of 500 kcal vs 750-1000 kcal in DPP) andencourages a progressive increase in exercise, rather than specifying aminimum amount of physical activity, as in DPP. Although the differencesbetween lifestyle intervention alone (placebo group) and PHEN/TPM ERwith lifestyle intervention to promote weight loss and prevent type 2diabetes were relatively small in the SEQUEL trial, treatment withPHEN/TPM ER should nevertheless be combined with lifestyle modificationto realize the full clinical benefits demonstrated in this study. Thesefindings have particular relevance to real world treatment decisions,since maintaining clinically meaningful weight loss through lifestylechanges alone is challenging (Norris S L, et al., Cochrane Database SystRev 2005; 18(2):CD005270). The robust clinical benefits observed with aneffective pharmacologic agent combined with lifestyle modification thusmay confer a significant advantage to improve outcomes in patients athigh risk of developing type 2 diabetes.

In general, PHEN/TPM ER was well tolerated, with no meaningfuldifferences in safety in the prediabetes and/or MetS cohort during 108weeks when compared with the overall SEQUEL population, and nodifferences between years 1 and 2 (Garvey et al., Am J Clin Nutr 2012;95(2):297-308). Given the high risk of type 2 diabetes, which confersextensive patient suffering and high societal costs, the potentialbenefit:risk ratio of weight-loss treatment could be particularlyfavorable in patients with prediabetes and/or MetS.

The SEQUEL study was limited to high-enrolling centers with high patientretention from CONQUER, so not all patients were eligible for theextension (Garvey et al., Am J Clin Nutr 2012; 95(2):297-308). Patientsenrolled at sites eligible to participate in SEQUEL had slightly greaterweight loss (˜1% across treatment arms) at CONQUER end point thanpatients at non-SEQUEL sites. In addition, a higher percentage ofPHEN/TPM ER-treated patients elected to continue in the study, so theoriginal 2:1:2 randomization ratio was not maintained in the SEQUELtrial. The overall enrolled population for the SEQUEL clinical trial waslarger than the subset of patients evaluated in this subanalysis; evenso, baseline demography, efficacy, and safety were similar to theoverall population, suggesting continuity across populations (Gadde etal., Lancet 2011, Garvey et al., Am J Clin Nutr 2012; 95(2):297-308).Because patients with type 2 diabetes were excluded, there were somesignificant differences, mostly in glycemic parameters, between thecohort included in this analysis and those who were excluded (Table 4).

TABLE 4 Baseline demographics of patients included vs. those excludedfrom the analysis Prediabetes and/or Metabolic Syndrome Cohort ExcludedCohort (n = 475) (n = 1973) Parameter Mean (SD) Mean (SD) P Value Age(years) 52.0 (10.4) 50.9 (10.4) 0.0457 Women, n (%)  308 (64.8) 1404(71.2)  0.0070 HDL-C (mmol/mol) 1.2 (0.3) 1.2 (0.4) 0.0100 Fastingglucose, 5.7 (0.7) 5.9 (1.3) 0.0007 mmol/L HbA_(1c) (%) 5.7 (0.5) 5.9(0.8) <0.0001 [mmol/L (SD)]  [39 (4.9)]  [41 (8.7)] Subjects with anti- 4 (0.8)  249 (12.6) <0.0001 diabetic medication use, n (%) Subjectswith lipid-  194 (40.8)  700 (35.5) 0.0293 lowering medication use, n(%)

Also, because the study involved active management to standards of care,changes in concomitant medications for treatment of hypertension,dyslipidemia, and hyperglycemia are likely to have affected relatedstudy variables, often narrowing the gap between PHEN/TPM ER-treatedpatients and those taking placebo. However, active management wasapplied by treatment-blinded clinicians across placebo and PHEN/TPM ERtreatment groups. Although these medication adjustments may affect someparameters, this also means that the study is largely representative ofthe type of care given in routine clinical practice, indicating thatclinical benefits seen here may also be achieved in a real-world setting(3). In a separate analysis of the overall SEQUEL population, includingthose with type 2 diabetes, the weight loss associated with PHEN/TPM ERtreatment induced improvement in cardiometabolic parameters even as useof medications to treat dysglycemia, hypertension, and dyslipidemia wasreduced as compared with placebo (40). This suggests that weight lossassociated with PHEN/TPM ER may lead to reduced medication burden forthe treatment of weight related comorbidities. Lastly, while 2 years islonger than any registration studies, it would be beneficial to havelonger term data to add to our understanding of the benefits and risksof prolonged PHEN/TPM ER use.

This study demonstrates that PHEN/TPM ER plus lifestyle modification wasgenerally well tolerated and produced significant weight loss through108 weeks in patients with prediabetes and/or MetS at baseline. Theability of PHEN/TPM ER to prevent progression to type 2 diabetes wasprofound, with both PHEN/TPM ER treatment groups exhibitingstatistically significant reductions in incidence rate in thesehigh-risk individuals with prediabetes and/or MetS, with greater weightloss leading to greater reductions in progression to type 2 diabetes.Concomitant improvements in glucose homeostasis, insulin sensitivity,and cardiometabolic-disease biomarkers were also seen. These dataindicate that adding PHEN/TPM ER to lifestyle modification mayconstitute a new and effective therapeutic approach in patients withobesity and cardiometabolic disease, even as an alternative to bariatricsurgery, by virtue of the ability of PHEN/TPM ER to produce substantialweight loss and to reduce risk of progression to type 2 diabetes inpatients at high risk.

Of the 866 subjects who completed CONQUER at eligible SEQUEL sites, 675(77.9%) elected to enroll in the SEQUEL extension study (Garvey et al.,Am J Clin Nutr 2012; 95:297-308). The SEQUEL cohort included 145 (21.5%)subjects with type 2 diabetes at baseline and 55 (8.1%) subjects who didnot meet criteria for either prediabetes or MetS; these individuals wereexcluded from the current analysis, leaving 475 (70.4%) at-risk subjectsas defined by either prediabetes or MetS criteria, including 316 withprediabetes, 451 with MetS, and 292 meeting criteria for bothprediabetes and MetS. Baseline demographics and clinical characteristicsfor subjects with prediabetes and/or MetS were similar among thetreatment arms (Table 1).

TABLE 1 Baseline demographics and clinical characteristics of the cohortwith prediabetes and/or MetS at baseline (ITT). PHEN/TPM PHEN/TPMPlacebo 7.5/46 15/92 Demographic or clinical characteristic (n = 159) (n= 115) (n = 201) Mean age, years (SD) 52.5 (9.7)  52.4 (10.9)  51.3(10.5) Women, n (%)  101 (63.5)   75 (65.2)  132 (65.7) Race, n (%)Caucasian  139 (87.4)  102 (88.7)  169 (84.1) Black   19 (11.9)  11(9.6)   27 (13.4) Other   2 (1.3)   3 (2.6)   7 (3.5) Mean weight, kg(SD) 102.9 (19.0) 104.4 (18.3) 103.4 (17.8) Mean BMI, kg/m² (SD) 36.1(4.5) 36.2 (4.5) 36.3 (4.4) Mean waist circumference, cm (SD) 113.7(12.9) 113.4 (12.3) 113.1 (11.9) Mean blood pressure (mmHg) Systolic(SD) 129.1 (14.4) 127.8 (12.0) 128.1 (13.0) Diastolic (SD) 80.9 (9.5)80.5 (9.2) 80.5 (8.4) Mean heart rate, bpm (SD)  70.4 (10.9) 72.8 (9.9) 72.5 (10.3) Mean total cholesterol, mg/dL (SD) 205.7 (41.9) 203.6(35.6) 204.0 (40.4) Mean LDL-C, mmol/L (SD)  3.3 (0.9)  3.2 (0.8)  3.2(0.9) Mean non-HDL-C, mmol/L (SD)  4.1 (1.1)  4.0 (0.9)  4.1 (1.0) MeanHDL-C, mmol/L (SD)  1.2 (0.3)  1.3 (0.3)  1.2 (0.28) Mean triglycerides,mmol/L (SD)  1.8 (0.7)  1.8 (0.8)  1.8 (0.8) Mean fasting glucose,mmol/L (SD)  5.7 (0.7)  5.8 (0.7)  5.7 (0.8) Mean glycated hemoglobin, %(SD) (mmol/mol [SD]) 5.7 (0.5) (39 [5.5]) 5.7 (0.4) (39 [4.4]) 5.7 (0.5)(39 [5.5]) Fasting insulin, pmol/L (SD) 122.2 J(80.6)  122.2 (90.3)119.5 (67.4) Mean hs-CRP, mg/L (SD)  5.4 (6.7)  6.6 (10.6)   6.2(7.8)^(†) Subjects with antidiabetes medication use, n (%)   1 (0.6)   1(0.9)  2 (1) Subjects with antihypertensive medication use, n (%)  106(66.7)   69 (60.0)  124 (61.7) Subjects with lipid-lowering medicationuse, n (%)   64 (40.3)   49 (42.6)   81 (40.3) LDL-C, LDL cholesterol.*Defined as subjects with prediabetes, MetS or both at baseline.^(†)There were missing values for hs-CRP for one subject in the 15/92group.

Treatment with PHEN/TPM ER induced significantly greater weight lossversus placebo in subjects in the prediabetes and/or MetS cohort. After108 weeks of treatment, this cohort lost 10.9% and 12.1% of their bodyweight in the 7.5/46 and 15/92 treatment arms, respectively, versus 2.5%in those subjects receiving placebo (ITT-MI; P<0.0001), with similarresults in the ITT-LOCF analysis (FIG. 1). The degree of weight loss inthe placebo and PHEN/TPM ER treatment arms was similar in subjects withprediabetes or MetS at baseline and in the overall SEQUEL population atweek 108 (26). No subjects experienced a BMI less than 18.5 kg/m2 atstudy end. For FIG. 1, P<0.0001 vs placebo for all time points assessed.LS, least-squares; LOCF, last observation carried forward; MI, multipleimputation; PHEN/TPM ER, phentermine and topiramate extended-release.

Although subjects in all treatment arms with prediabetes and/or MetSwere administered a moderate lifestyle intervention program, thecumulative incidence rates of type 2 diabetes (FIG. 2A) was markedlyreduced in subjects randomized to PHEN/TPM ER when compared with placeboover 108 weeks. The annualized incidence rate of type 2 diabetes in thispopulation was 6.1, 1.8, and 1.3 for placebo, 7.5/46, and 15/92(reductions of 70.5% with 7.5/46 and 78.7 with 15/92; P<0.05 vs placebo;ITT). The absolute risk reduction of progression to type 2 diabetes was11.4%, 3.5%, and 2.5% for placebo, 7.5/46 (95% CI: 1.8%, 13.9% vsplacebo), and 15/92 (95% CI: 3.5%, 14.3% vs placebo). In subjectsmeeting criteria for prediabetes, subjects receiving 7.5/46 had a 48.6%reduction in the annualized incidence rate of type 2 diabetes and thosereceiving 15/92 had an 88.6% reduction versus placebo (FIG. 2B).Furthermore, subjects with MetS receiving 7.5/46 had a 76.6% reductionand those receiving 15/92 had a 79.7% reduction (FIG. 2B). The magnitudeof effect for type 2 diabetes prevention was related to the degree ofweight loss achieved at 108 weeks in the ITT-MI population (FIG. 2C).Error bars represent 95% CI. Annualized incidence rate of type 2diabetes was based on first occurrence of 2 consecutive FG ≥7.0 mmol/L,2 consecutive OGTT ≥11.1 mmol/L, or taking antidiabetic medications atend point. Greater weight loss was associated with a greater reductionin incidence of type 2 diabetes regardless of randomization group.Subjects achieving <5% weight loss had the highest annualized type 2diabetes incidence rate: 6.3. The lowest incidence rate, 0.9, wasobserved with weight loss of ≥15%; an intermediate type 2 diabetesincidence rate of 1.3 was seen among those with ≥5% to <10% or ≥10% to<15% weight loss (ITT-MI; P<0.05 vs <5% weight loss for allcomparisons). In the ITT-LOCF analysis, annualized incidence rate oftype 2 diabetes was 6.1 (SD: 1.3), 1.8 (SD: 0.9), 0.6 (SD: 0.6), and 1.3(SD: 0.8) for the <5%, ≥5% to <10%, ≥10% to <15%, and ≥15% groups,respectively. For FIGS. 2A-2C *P=0.0125 vs placebo; †P=0.0093 vsplacebo; ‡P=0.0007 vs placebo; § P<0.05 vs <5% weight loss for allcomparisons. ITT is intent to treat; CI is confidence interval; FG isfasting glucose; OGTT is oral glucose tolerance test; and PHEN/TPM ER isphentermine and topiramate extended-release.

PHEN/TPM ER also significantly improved cardiometabolic disease riskfactors versus placebo in subjects with prediabetes and/or MetS. Asshown in FIGS. 3A-C, which show glycemic and lipid parameters at week108 in the cohort with prediabetes and/or Metabolic Syndrome atbaseline, when compared with placebo, fasting glucose, fasting insulin,2-hour post-OGTT glucose, fasting triglycerides, and HDL-C were allimproved in the PHEN/TPM ER groups over 108 weeks (ITT-MI). Reductionsin SBP (mm Hg) of −3.9 (SE: 0.98), −5.0 (SE: 1.14), −5.1 (SE: 0.91) andreductions in DBP of −3.7 (SE: 0.73), −3.6 (SE: 0.82), and −3.8 (SE:0.61), were observed with placebo, 7.5/46, and 15/92, respectively (notsignificant vs placebo; ITTMI; Table 2). Subjects treated with PHEN/TPMER also had reduced waist circumference, HbA1c, and Homeostasis Model ofAssessment-Insulin Resistance and increased Whole Body InsulinSensitivity Index versus placebo at week 108 (ITT-MI; Table 2). Datarepresent least-squares mean change in subjects with prediabetes orMetabolic Syndrome at baseline, intent-to-treat with multipleimputation. HOMA-IR is Homeostasis Model of Assessment-InsulinResistance; WBISI is Whole Body Insulin Sensitivity Index.

Table 2. Changes from baseline to week 108 in secondary end points inthe cohort with prediabetes and/or Metabolic Syndrome at baseline(ITT-MI).

TABLE 2 Changes from baseline to week 108 in secondary end points in thecohort with prediabetes and/or Metabolic Syndrome at baseline (ITT-MI).PHEN/TPM PHEN/TPM Placebo ER 7.5/46 ER 15/92 (n = 159) (n = 115) (n =201) Mean waist −4.6 (0.65) −11.3 (0.76)* −12.8 (0.58)* circumference,cm (SE) Mean HbA_(1c), % (SE) 0.07 (0.02) −0.03 (0.03)  −0.09 (0.02) [mmol/mol (SE)] [0.8 (0.2)] [−0.3 (0.3)]^(† ) [−1.0 (0.2)]* Meansystolic blood −3.9 (0.98) −5.0 (1.14) −5.1 (0.91) pressure, mm Hg (SE)Mean diastolic blood −3.7 (0.73) −3.6 (0.82) −3.8 (0.61) pressure, mm Hg(SE) Mean HOMA-IR (SE) −0.8 (0.21)  −1.7 (0.25)^(‡)  −1.8 (0.21)^(§)Mean WBISI (SE)  1.6 (0.36)  2.4 (0.47)   3.4 (0.33)^(¶) *P < 0.0001,^(†)P = 0.0037, ^(‡)P = 0.0047, ^(§)P = 0.0006, ^(¶)P = 0.0003 vsplacebo for all comparisons.

Similar results were seen in the ITT-LOCF analysis (Table 3). Amongthose with MetS at baseline, by week 108, a significantly greaterpercentage of subjects treated with 7.5/46 (22.4%) and 15/92 (27.6%)achieved remission of MetS compared with placebo (9.2%; P=0.0001 vsplacebo). Also, at week 56 in subjects with prediabetes and/or MetS,PHEN/TPM ER was associated with lower hs-CRP values (−1.7, −2.7, and−2.2 mg/dL in placebo, 7.5/46, and 15/92, respectively; P=notsignificant vs placebo; ITT-MI), lower fibrinogen levels (−10.1, −11.3,and −15.2 mg/dL in placebo, 7.5/46, and 15/92; P=not significant vsplacebo; ITT-MI), and increased adiponectin concentrations (0.4, 2.2,and 2.9 Og/mL in placebo, 7.5/46, and 15/92; P<0.0001 vs placebo;ITT-MI). In FIGS. 3A-C error bars represent 95% CI. *P=0.0474;†P<0.0001; ‡P=0.0028; § P=0.0126; ¶P=0.0012, #P=0.0419; ∥P=0.0004;**P=0.0262; ††P=0.0009 vs placebo for all comparisons. ITT, intent totreat; MI, multiple imputation; CI, confidence interval; OGTT, oralglucose tolerance test; LS, least-squares; PHEN/TPM ER, phentermine andtopiramate extended-release; HDL, high-density lipoprotein.

TABLE 3 Changes from baseline to week 108 in secondary end points in thecohort with prediabetes and/or Metabolic Syndrome at baseline(ITT-LOCF). PHEN/TPM PHEN/TPM Placebo ER 7.5/46 ER 15/92 (n = 159) (n =115) (n = 201) Mean waist circumference, cm (SE) −4.4 (0.63) −11.4(0.74)* −12.9 (0.56)* Mean fasting glucose, mmol/L (SE) 0.01 (0.05)−0.18 (0.06)^(† ) −0.32 (0.04)* Mean 2-hour OGTT glucose, mmol/L (SE)−0.37 (0.14)  −0.57 (0.16)  −1.01 (0.12)^(‡ ) Mean HbA_(1c), % (SE)[mmol/mol (SE)] 0.08 (0.02) [0.9 (0.2)] −0.03 (0.02) [−0.3 (0.2)]^(§)−0.09 (0.02) [−1.0 (0.2)]* Mean fasting insulin, ρmol/L (SE) −18.4(5.0)  −39.2 (5.9)^(¶ )  −37.3 (4.5)^(# )  Mean 2-hour OGTT insulin,ρmol/L (SE) −157.2 (30.7)  −264.0 (36.1)^(∥ ) −327.0 (27.3)*  Meansystolic blood pressure, mm Hg (SE) −4.1 (0.92) −4.9 (1.08) −5.2 (0.82)Mean diastolic blood pressure, mm Hg (SE) −3.7 (0.66) −3.2 (0.77) −3.8(0.58) Mean HOMA-IR (SE) −0.8 (0.21)  −1.7 (0.25)**  −1.7 (0.19)^(††)Mean WBISI (SE)  1.5 (0.42)    2.8 (0.49)^(‡‡)    3.6 (0.37)^(§§) Meannon-HDL-C, % (SE) −9.1 (1.42) −9.9 (1.67) −10.0 (1.26)  Mean HDL-C, %(SE)  6.6 (1.54) 10.0 (1.81)  14.2 (1.37)^(§§) Mean triglycerides, %(SE) −1.1 (2.77)  −13.3 (3.26)^(¶¶) −17.7 (2.46)* *P < 0.0001, ^(†)P =0.011, ^(‡)P = 0.005, ^(§)P = 0.0015, ^(¶)P = 0.0075, ^(#)P = 0.0052,^(∥)P = 0.025. **P = 0.0087, ^(††)P = 0.0033, ^(‡‡)P = 0.0441, ^(§§)P =0.0002, ^(¶¶)P = 0.0047 vs placebo for all comparisons.

The daily dose of, phentermine, can be any appropriate daily dose. Forexample, the daily dose of the sympathomimetic agent, for example,phentermine, can be from about 2 mg to about 1,500 mg, for example, adaily dose of about 2 mg to about 20 mg. The daily dose of thesympathomimetic agent can be increased if and when the daily dose oftopiramate is increased, although this is not required unless otherwisespecified. The ratio of topiramate to phentermine in the different dailydoses may be constant, for example, if the first daily dose is 23 mg oftopiramate and 3.75 mg phentermine, for a weight of phentermine totopiramate ratio of about 16% (i.e. the weight of the phentermine isabout 16% of the weight of the topiramate), then one or more of thesecond, third, and fourth daily doses can also have about a 16% weightratio of phentermine to topiramate. Other ratios may also be used, forexample, about 10-20%, about 13-17%. The ratio may be maintained for oneor more of the second, third and fourth doses. For example, the seconddaily dose may be about 7.5 mg phentermine and 46 mg topiramate, thethird may be about 11.25 mg phentermine and about 69 mg topiramate andthe fourth about 15 mg phentermine and about 92 mg topiramate, eachdaily dose having a ratio of about 16% (the weight of phentermine beingabout 16% of the weight of phentermine).

Subjects who are candidates to maintain either the daily dose of 46 mgtopiramate with 7.5 mg phentermine or the daily dose of 92 mg topiramatewith 15 mg phentermine can maintain that regimen. Subjects who respondto the 7.5 mg phentermine/46 mg topiramate daily dose may continuetaking that daily dose after the 3 month period for an additional periodof time, for example, for 3, 6, 9, 12, 18, 24, or 36 additional monthsor more.

The phentermine and topiramate used in the dosing regimens and methodsdescribed herein can be administered in any suitable dosage form,depending on the desired route of administration. For example, tablets,capsules, caplets, elixirs, syrups, sachets, granules, powders, pellets,and beads are all suitable for oral administration. Dosage forms forthese and other routes and modes of administration are discussed, forexample, in Remington: The Science and Practice of Pharmacy, which ishereby incorporated by reference in its entirety.

Topiramate can be present in a controlled release dosage form, such as asustained release form, a delayed release form, or a dosage form withboth delayed and sustained release. Controlled release forms can be anycontrolled release form, and can be prepared by any preparation methodknown in the art. Some controlled release forms include topiramatedispersed within a matrix of one or more controlled release polymers,for example, one or more hydrolyzable or degradable polymers, such asone or more hydrophilic polymers. Other controlled release forms includea topiramate containing dosage form coated with one or more controlledrelease polymers. Exemplary hydrophilic polymers useful for this purposeinclude cellulose polymers, such as one or more of hydroxypropylcellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose,methyl cellulose (METHOCEL®), ethyl cellulose, cellulose acetate,cellulose acetate phthalate, and sodium carboxymethylcellulose, acrylicpolymers and copolymers, such as polymers or copolymers of one or moreof (meth)acrylic acid, methyl(meth) acrylate, and ethyl (meth)acrylate,vinyl polymers and copolymers, such polymers with one or more ofpolyvinyl pyrrolidone (POVIDONE® and POVIDONE® K30), polyvinyl acetate,and ethylene vinyl acetate.

Controlled release dosage forms, such as sustained release dosage forms,can also include additional excipients such one or more binders,diluents, bulking agents, glidents, lubricant, taste-modifying agents,flavorings, colorings, and the like. Such agents can be useful in themanufacturing process of the controlled release dosage form,commercially beneficial, for example, to provide a commerciallydesirable appearance, taste, or both. Many examples of such excipientsare known in the art, and are discussed, for example, in Remington: TheScience and Practice of Pharmacy, which is hereby incorporated byreference in its entirety.

Specific examples of controlled release dosage forms of topiramateinclude polymer matrices that contain the topiramate and a controlledrelease polymer, tablets coated with a controlled release polymer,osmotic tablets, and polymer coated beads. In one aspect controlledrelease topiramate beads are made using an extrusion spheronizationprocess to produce a matrix core comprised of topiramate, 40.0% w/w;microcrystalline cellulose (AVICEL® PH102), 56.5% w/w; and METHOCEL™ A15LV, 3.5% w/w. The topiramate cores are then coated with ethyl cellulose,5.47% w/w, and Povidone K30, 2.39% w/w. Such dosage forms can beprepared by methods known in the art, for example, methods described inU.S. Pat. Pub. No. 2009/0304785, which is hereby incorporated byreference.

In one example the composition of the topiramate beads may be 36.85% w/wtopiramate, 52.05% w/w microcrystalline cellulose, 3.22% w/wmethylcellulose, 5.47% w/w ethyl cellulose, and 2.39% w/wpolyvinylpyrrolidone (PVP).

The phentermine can be present in the same dosage form as the topiramateor in a different dosage form. When the phentermine is in a differentdosage form from the topiramate, the type of dosage form used for thephentermine can be the same or different from the type of dosage formused for the topiramate. For example, topiramate can be present in acapsule and phentermine can be present in a solution. In that example,the topiramate can be administered orally and the phentermine can beadministered intra-muscularly. As another example, the topiramate andphentermine can be present in the same dosage form, such as a powder,bead, or granule, or in the same unit dosage form, such as a capsule, ortablet. When present in a tablet form the tablet can be a multilayertable, for example, a bilayer tablet having an immediate release portioncontaining the phentermine and a sustained release portion containingthe topiramate. A tablet-in-tablet formulation can also be used, wherethe core comprises a therapeutically effective amount of topiramate thatis surrounded by a layer comprising a therapeutically effective amountof phentermine. The topiramate and phentermine can be in direct contactor may be separated by a barrier layer. The core can contain bothtopiramate and one or more pharmaceutically acceptable excipients. Thetablet can be coated with a rapidly dissolving coating or film.

The phentermine can be administered in an immediate release form dosageform. An exemplary immediate release form is an inert bead, such as anon-pareil or sugar sphere, coated with the phentermine, to form one ormore coated beads. Additional coating agents, such as film-formers,diluents, plasticizers, binders, coating aids, adhesion aids, and thelike, can also be present in the coating of the phentermine coatedbeads. Further, additional coating layers, such as film-coats ortopcoats, can be present either on top of the phentermine coating orbetween the inert bead and the phentermine coating. Phentermine coatedbeads can be, for example, mixed with one or more tableting excipients,such as one or more binders, lubricants, glidant, etc., and compressedinto one or more tablets. Phentermine coated beads can also be preparedas one or more capsules, for example, by filling one or more capsuleshells, such as gelatin capsule shells, with the phentermine coatedbeads. In one aspect, phentermine hydrochloride is coated onto sugarspheres to provide immediate release phentermine beads. These beads arecombined with the topiramate beads described above and then encapsulatedinto each of a plurality of capsules, with each capsule containing 3.75mg phentermine (as 4.92 mg phentermine HCl) and 23 mg topiramate or7.5/46, 11.25/69 and 15/92.

When phentermine is in the same dosage form as the topiramate, such as aunit dosage form with topiramate and phentermine, the unit dosage formcan contain a controlled release portion of topiramate and an immediaterelease portion of phentermine. For example, one or more polymer coatedbeads containing topiramate and one or more sympathomimetic agent coatedbeads can be present in the same dosage form. In active ingredients mayinclude methylcellulose, sucrose, starch, microcrystalline cellulose,ethylcellulose, povidone, gelatin, talc, and titanium dioxide.

One or more dosage forms of topiramate and phentermine, for example, foruse in one or more of the dosing regimens or methods described herein,such as the dosage forms described herein, can be packaged into aconvenient packaging for delivery to or use by one or more physicians,subjects, nurses, health-care professionals, etc. Such packaging caninclude one or more sealed containers, each containing one or moredosage forms of topiramate, such as the dosage forms described herein.

Upon oral administration of a dose of PHEN-TPM-ER 15 mg/92 mg, theresulting mean plasma phentermine maximum concentration (C_(max)), timeto C_(max) (T_(max)), area under the concentration curve from time zeroto the last time with measurable concentration (AUC_(0-t)), and areaunder the concentration curve from time zero to infinity (AUC_(0-□)) are49.1 ng/mL, 6 hr, 1990 ng·hr/mL, and 2000 ng·hr/mL, respectively. A highfat meal does not affect phentermine pharmacokinetics for PHEN/TPM ER 15mg/92 mg. Phentermine pharmacokinetics is approximatelydose-proportional from PHEN/TPM ER 3.75 mg/23 mg to phentermine 15mg/topiramate 100 mg. Upon dosing phentermine/topiramate 15/100 mg fixeddose combination capsule to steady state, the mean phentermineaccumulation ratios for AUC and C_(max) are both approximately 2.5.

Upon oral administration of a single Qsymia 15 mg/92 mg, the resultingmean plasma topiramate C_(max), T_(max), AUC_(0-t), and AUC_(0-∞), are1020 ng/mL, 9 hr, 61600 ng·hr/mL, and 68000 ng·hr/mL, respectively. Ahigh fat meal does not affect topiramate pharmacokinetics for PHEN/TPMER 15 mg/92 mg. Topiramate pharmacokinetics is approximatelydose-proportional from PHEN/TPM ER 3.75 mg/23 mg to phentermine 15mg/topiramate 100 mg. Upon dosing phentermine 15 mg/topiramate 100 mgfixed dose combination capsule to steady state, the mean topiramateaccumulation ratios for AUC and C_(max) are both approximately 4.0.

SEQUEL was a 52-week extension of the 56-week, phase 3, randomized,double-blind, parallel-group, placebo-controlled CONQUER trial (Gadde KM, et al., Lancet 2011; 377(9774):1341-1352 and Garvey W T, et al. Am JClin Nutr 2012; 95(2):297-308.). The selection process for the 36 SEQUELsites was based on high initial CONQUER enrollment and subjectretention. Subject outcomes and randomization remained blinded duringthis process. All subjects who completed CONQUER on treatment at thissubset of 36 sites were eligible to enroll in the SEQUEL extension study(Garvey et al. 2012). All subjects entering SEQUEL maintained theiroriginal randomized treatment assignment from CONQUER (in a 2:1:2 ratio,stratified by gender and diabetic status) of once-daily oral placebo,PHEN 7.5 mg/TPM ER 46 mg, or PHEN 15 mg/TPM ER 92 mg (placebo, 7.5/46,and 15/92, respectively), plus lifestyle-modification counseling basedon the LEARN (lifestyle, exercise, attitudes, relationships, andnutrition) program (Brownell K. The LEARN Program for Weight Management.Dallas, Tex., The Life Style Company 2000), for an additional 52 weeks,resulting in 108 weeks of treatment. A computer-generated algorithm hadbeen used to randomize subjects to study treatment at the beginning ofthe CONQUER study.

Investigators and subjects remained blinded to treatment assignment.Study drug compliance (assessed by count of capsules returned bysubject) and lifestyle counseling were addressed at each study visit,conducted every 4 weeks. At baseline (CONQUER week 0), subjects wereoverweight or obese adults (aged 18-70 years), with body mass indices of27-45 kg/m2, and ≥2 of the following weight-related comorbidities:central adiposity, dyslipidemia, hypertension, or type 2 diabetes.Subjects were actively managed to standard of care for theircomorbidities, including the option to add, discontinue, or dose-adjustmedications. The trials were approved by each center's institutionalreview board and overseen by an independent data safety review board.All subjects provided written informed consent. The first subject wasenrolled into this study on Dec. 6, 2008, and the last subject completedthe study on Jun. 8, 2010.

The subgroup analyses presented in this article were performed on thesubset of subjects with prediabetes and/or MetS at baseline who electedto enroll in the SEQUEL study. Subjects with a medical history of type 2diabetes at baseline were excluded from this analysis. The criteria forprediabetes for the study were as defined by the American DiabetesAssociation: IFG (fasting glucose levels 100-125 mg/dL [5.6-6.9 mmol/L])or IGT (blood glucose 140-199 mg/dL [7.8-11.0 mmol/L] 2 hours following75-g glucose load during an oral glucose tolerance test [OGTT]). Thediagnosis of MetS was made when ≥3 of the following 5 criteria were met:waist circumference ≥102 cm in men or ≥88 cm in women; triglycerides≥150 mg/dL (1.7 mmol/L) or taking ≥1 lipid-lowering medication;high-density lipoprotein cholesterol (HDL-C) <40 mg/dL (1.0 mmol/L) inmen or <50 mg/dL (1.3 mmol/L) in women or taking ≥1 lipid-loweringmedication; systolic blood pressure (SBP) ≥130 mm Hg or diastolic bloodpressure (DBP) ≥85 mm Hg or taking ≥1 antihypertensive medication;fasting glucose ≥100 mg/dL (5.6 mmol/L) or taking drug treatment forelevated glucose (Alberti et al., Circulation 2009; 120:1640-1645). Theprimary end point was percent weight loss from baseline, which wasassessed after 108 weeks (or early termination) in the SEQUEL study.Prespecified secondary end points were assessed at baseline, week 56,and week 108 (or early termination) and included annualized incidencerate of progression to type 2 diabetes and changes in glycemia, lipidparameters, blood pressure, and waist circumference (25,26). Remissionof MetS, i.e., no longer meeting the diagnostic criteria as evidenced bysatisfying only ≤2 of these criteria, at week 108 was also assessed.Finally, at week 56, high-sensitivity C-reactive protein (hs-CRP) andfibrinogen, both of which are inflammatory markers associated with MetS,were measured, as was adiponectin, which is decreased in subjects withobesity and cardiometabolic disease (Sutherland J P, et al. Metab SyndrRelat Disord 2004; 2(2):82-104).

For analyses of glucose and insulin as measured by OGTT (75-g loadingdose), the change in each parameter from the pre-glucose loading dosesample to the sample obtained 2 hours after the glucose loading dose ateach applicable visit was calculated. OGTT was measured at baseline,week 4, week 56, and week 108. Fasting blood glucose was measured atbaseline and weeks 4, 16, 28, 40, 56, 48, 96, and 108. Subjects wereconsidered to have progressed to type 2 diabetes if their blood glucosewas ≥126 mg/dL under fasting conditions during ≥2 consecutivemeasurements and/or ≥200 mg/dL at 2 hours after an OGTT.

Statistical analysis. Primary and secondary end points were assessed inthe intent-to-treat (ITT) population using analysis of covariance(ANCOVA) with terms for treatment group and baseline value. Toaccommodate missing data, multiple imputation (MI) was applied to allend points where missing data were apparent using, specifically, a2-step imputation process with m=5 imputations per step (Elobeid M A, etal. PLoS ONE 2009; 4(8):e6624.). In the first step, data were imputed tocreate a monotone missing data pattern by using a Markov chain MonteCarlo algorithm. In the second step, remaining missing data were imputedusing Rubin's regression method (Rubin D B. Multiple Imputation forNonresponse in Surveys. Wiley Series in Probability and MathematicalStatistics. New York, John Wiley & Sons, 1987). The complete imputeddatasets were then analyzed by ANCOVA as described above, and theresults from analysis of the separate imputed datasets were pooled intosingle estimates and tested as described by Schafer (Schafer J L.Analysis of Incomplete Multivariate Data. (Monographs on Statistics andApplied Probability 72) London, Chapman & Hall/CRC, 1997).

While various embodiments have been described in detail in order toexplain the invention, such embodiments are not intended to be limitingunless otherwise specified. Indeed, a person of skill in the art willrecognize that modifications, additions, and substitutions can beimplemented without altering the scope or spirit of the invention. Forexample, while embodiments featuring one or more sympathomimetic agentshave been described with reference to phentermine and particular dosagesthereof, other sympathomimetic agents can be used in appropriate dosagesto achieve similar results.

1. A method of delaying the progression from prediabetes to type 2diabetes in a patient, comprising: identifying a patient havingprediabetes and administering to the patient an oral dosage formcomprising immediate release phentermine and controlled releasetopiramate.
 2. The method of claim 1 wherein the oral dosage formcomprises: a) 3.75 mg immediate release phentermine in combination with23 mg controlled release topiramate, or b) 7.5 mg immediate releasephentermine in combination with 46 mg controlled release topiramate, orc) 11.25 mg immediate release phentermine in combination with 69 mgcontrolled release topiramate, or d) 15 mg immediate release phenterminein combination with 92 mg controlled release topiramate.
 3. The methodof claim 2 wherein the oral dosage form is administered to the patientfor at least 3 months.
 4. The method of claim 1 wherein a first oraldosage form is administered to the patient for 1 to 2 weeks and a secondoral dosage form is administered to the patient for 3 months and whereinthe first oral dosage form comprises 3.75 mg immediate releasephentermine in combination with 23 mg controlled release topiramate andthe second oral dosage form comprises 7.5 mg immediate releasephentermine in combination with 46 mg controlled release topiramate. 5.The method of claim 1 wherein the step of identifying a patient havingprediabetes comprises determining that the patient has at least one ofthe following: (i) HbA1c levels that are between 5.7% and 6.4%; (ii)plasma glucose levels between 7.8 mmol/L and 11 mmol/L; and (iii) bloodglucose levels less between 6.1 mmol/L and 7.0 mmol/L.
 6. The method ofclaim 1 further comprising continuing to administer the oral dosage formto the patient following the onset of type 2 diabetes and therebyreducing the severity of type 2 diabetes symptoms in the patient.
 7. Themethod of claim 3 wherein the administering prevents the onset of type 2diabetes in the patient for the at least 3 months.
 8. The method ofclaim 7 wherein the onset of type 2 diabetes is prevented if the patienthas at least one of the following after the at least 3 months: (i) HbA1clevels that are 6.4% or less; (ii) plasma glucose levels that are 11mmol/L or less; and (iii) blood glucose levels that are 7.0 mmol/L orless.
 9. The method of claim 1 further comprising achieving in thepatient at least one of the following: lowering of hs-CRP values to lessthan 3.0 mg/L, lowering fibrinogen levels to at least 400 mg/dL andincreasing adiponectin concentrations to a level that is higher than thelevel measured in the patient prior to administering the oral dosageform to the patient.
 10. The method of claim 1 further comprisingachieving in the patient an improvement in at least one of thefollowing: fasting glucose levels, fasting insulin levels, 2-hourpost-OGTT glucose levels, fasting triglycerides levels or HDL-C levels.11. A method of delaying the progression from MetS to type 2 diabetes ina patient comprising: identifying a patient having MetS andadministering to the patient an oral dosage form comprising immediaterelease phentermine and controlled release topiramate.
 12. The method ofclaim 11 wherein the oral dosage form comprises: a) 3.75 mg immediaterelease phentermine in combination with 23 mg controlled releasetopiramate, or b) 7.5 mg immediate release phentermine in combinationwith 46 mg controlled release topiramate, or c) 11.25 mg immediaterelease phentermine in combination with 69 mg controlled releasetopiramate, or d) 15 mg immediate release phentermine in combinationwith 92 mg controlled release topiramate.
 13. The method of claim 12wherein the oral dosage form is administered to the patient for at least3 months.
 14. The method of claim 11 wherein a first oral dosage form isadministered to the patient for 1 to 2 weeks and a second oral dosageform is administered to the patient for 3 months and wherein the firstoral dosage form comprises 3.75 mg immediate release phentermine incombination with 23 mg controlled release topiramate and the second oraldosage form comprises 7.5 mg immediate release phentermine incombination with 46 mg controlled release topiramate.
 15. The method ofclaim 11 wherein the step of identifying a patient having MetS comprisesdetermining that the patient has at least three of the following: (i)waist circumference of at least 102 cm if the patient is male or atleast 88 cm if the patient is female; (ii) triglyceride level of 150mg/dL or higher; (iii) HDL cholesterol levels below 40 mg/dL if thepatient is a male or below 50 mg/dL if the patient is a female or takinglipid lowering medication; (iv) systolic blood pressure of 130 mm Hg orgreater, or diastolic blood pressure of 85 mm Hg or greater or takingantihypertensive medication; and (v) fasting blood glucose levels of 100mg/dL or greater or taking medication for elevated glucose.
 16. Themethod of claim 11 further comprising achieving in the patient at leastone of the following: lowering of hs-CRP values to less than 3.0 mg/L,lowering fibrinogen levels to at least 400 mg/dL and increasingadiponectin concentrations to a level that is higher than the levelmeasured in the patient prior to administering the oral dosage form tothe patient.
 17. The method of claim 11 further comprising continuing toadminister the oral dosage form to the patient following the onset oftype 2 diabetes and thereby reducing the severity of type 2 diabetessymptoms following onset of diabetes in the patient.
 18. The method ofclaim 13 wherein the administering prevents the onset of type 2 diabetesin the patient the at least 3 months.
 19. The method of claim 11 whereinthe patient achieves remission of MetS.
 20. The method of claim 11further comprising achieving in the patient an improvement in at leastone of the following over the measurements for the patient prior toadministering the oral dosage form to the patient: fasting glucoselevels, fasting insulin levels, 2-hour post-OGTT glucose levels, fastingtriglycerides levels or HDL-C levels.